A phase II randomized study of avelumab plus entinostat versus avelumab plus placebo in patients (pts) with advanced epithelial ovarian cancer (EOC ).

person Karen Anne Cadoo Memorial Sloan Kettering Cancer Center, New York, NY info_outline Karen Anne Cadoo, Michael L. Meyers, Robert Allen Burger, Deborah Kay Armstrong, Richard T. Penson, Michael S. Gordon, Gini F. Fleming, John William Moroney, Erika Paige Hamilton, Linda R. Duska, Robert Michael Wenham, Serap Sankoh, Susan Brouwer, Peter Ordentlich, Carol Aghajanian, Ursula A. Matulonis

Authors person Karen Anne Cadoo Memorial Sloan Kettering Cancer Center, New York, NY info_outline Karen Anne Cadoo, Michael L. Meyers, Robert Allen Burger, Deborah Kay Armstrong, Richard T. Penson, Michael S. Gordon, Gini F. Fleming, John William Moroney, Erika Paige Hamilton, Linda R. Duska, Robert Michael Wenham, Serap Sankoh, Susan Brouwer, Peter Ordentlich, Carol Aghajanian, Ursula A. Matulonis Organizations Memorial Sloan Kettering Cancer Center, New York, NY, Syndax Pharmaceuticals, Inc., New York, NY, Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University of Pennsylvania, Philadelphia, PA, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, Harvard Medical School, Boston, MA, Pinnacle Oncology Hematology, Arizona Center for Cancer Care, HonorHealth Research Institute Clinical Trials Program, Virginia G. Piper Cancer Center, Scottsdale, AZ, The University of Chicago Medicine, Chicago, IL, U.S. Naval Hospital Naples Italy, Fpo, AE, Italy, Tennessee Oncology, PLLC and Sarah Cannon Research Institute, Nashville, TN, University of Virginia, Charlottesville, VA, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, Syndax Pharmaceuticals, Inc., Waltham, MA, Syndax Pharmaceuticals, Lexington, MA, Dana-Farber Cancer Institute, Boston, MA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Preclinical evidence suggests that combining avelumab (A), a human anti-PD-L1 monoclonal antibody, and entinostat (E), a class I selective histone deacetylase (HDAC) inhibitor, may increase tumor immunogenicity and responsivity to checkpoint inhibition. This study evaluated whether A+E would lead to improved progression free survival (PFS) vs A in pts with advanced EOC. Methods: Pts with EOC which had progressed or recurred after 1st-line platinum-based chemotherapy and received 3- 6 lines of therapy were randomized 2:1 to receive A (10 mg/kg IV Q2W) plus E (5 mg PO QW) or A plus placebo (P). Treatment continued until disease progression (PD) or unacceptable toxicity. The primary endpoint was PFS (investigator-assessed, RECIST 1.1), stratifying on the presence/absence of bulky disease (tumor ≥ 50 mm) and platinum-refractory disease. The hypothesis was that the combination would reduce the hazard of PD or death by 43%, representing a 75% improvement in median PFS. 97 events (from 120 pts) provided 90% power with 1-sided significance level of 0.10. Secondary endpoints included ORR, duration and time to response, toxicity, clinical benefit rate, and OS. Results: 126 pts were enrolled, median age 63 yrs (range 43-82), median 4 prior lines, 83% serous histology. Median PFS was 1.64 and 1.51 mos for A+E and A+P, respectively (p = 0.31; HR 0.90, 95% CI: 0.58-1.39). No significant differences in ORR (6% vs 5%), or OS (NE vs 11.3 mos) were observed. 4 pts (3%) had clear cell EOC, with no responses observed. The incidence of related adverse events (AEs) was higher in the A+E arm compared to A+P (any grade: 93% vs 78%, Grade 3/4: 41% vs 10%), and the most frequent (≥20%) related AEs with A+E were fatigue (46%), nausea (31%), diarrhea (26%), anemia (26%), and chills (20%). Grade 3/4 related AEs occurring in ≥5% with A+E were fatigue (9%), and neutropenia (8%). 47% of pts in A+E arm required E dose holds/reductions. Discontinuations due to AEs were similar between arms (21% vs 17.5% for A+E and A+P, respectively), as was duration of study therapy (median 4 and 5 cycles started). Conclusions: In pts with heavily pretreated EOC, median PFS was not prolonged when E was added to A compared to A alone and the combination resulted in greater toxicity. Clinical trial information: NCT02915523